Transdermal delivery system for hormones and steroids

ABSTRACT

A transdermal delivery system comprising a composition comprising a pharmacological agent and a penetration enhancer wherein the penetration enhancer comprises polyethylene glycol (PEG) of average molecular weight no more than 300.

FIELD

This invention relates to a transdermal delivery system and to a methodof transdermal delivery of hormones and steroids.

BACKGROUND

Steroids and hormones include sex hormones and certain adrenocorticalhormones (corticosteroids). The corticosteroids have numerous anddiversified physiological functions and pharmacological effects. Theyinfluence carbohydrate, protein, fat, and purine metabolism; electrolyteand water balance; and the functions of the cardiovascular system, thekidney, skeletal muscle, nervous system, and other organs and tissues.Therapeutically, the corticosteroids are used for treating hormonalinsufficiencies, inflammation, and other conditions, whereas the sexhormones are widely used for contraception and hormonal insufficiencies,as well as for treating other conditions.

The two main classes of sex steroids are androgens and estrogens, ofwhich the most important human derivatives are testosterone andestradiol (17β-estradiol), respectively. Other contexts will includeprogestagen as a third class of sex steroids, distinct from androgensand estrogens. Progesterone is the only naturally-occurring humanprogestagen. Progestins are synthetic sex hormones used in contraceptioneither alone or with estradiol. Androgens are often referred to as “malesex hormones”, since they have masculinizing effects, while estrogensand progestagens are considered “female sex hormones” although all typesare present in each gender, albeit at different levels. Androgens may beused in treatment of reduced libido or in treatment of depression inboth men and women.

Administration of hormones and steroids through the skin (‘transdermaldelivery’) has received increased attention because it not only providesa potentially simple dosage regime but it also provides a relativelycontrolled route for release of a hormone into the systemic circulation.However, transdermal drug delivery is complicated by the fact that theskin behaves as a natural barrier and therefore transport of agentsthrough the skin is a complex mechanism.

Structurally, the skin consists of two principle parts, a relativelythin outermost layer (the ‘epidermis’) and a thicker inner region (the‘dermis’). The outermost layer of the epidermis (the ‘stratum corneum’)consists of flattened dead cells which are filled with keratin. Theregion between the flattened dead cells of the stratum corneum is filledwith lipids which form lamellar phases that are responsible for thenatural barrier properties of the skin.

For effective transdermal delivery of a pharmacological agent that isapplied to the surface of the skin (‘topical application’), the agentmust partition firstly from the vehicle into the stratum corneum, itmust typically then diffuse within the stratum corneum beforepartitioning from the stratum corneum to the viable epidermis.

A transdermal “patch” typically consists of a matrix or reservoircontaining the drug to be administered, together with a backing layer,an adhesive and a protective release liner. Release membranes may alsobe incorporated. The delivery of drugs through these systems is eitherthrough passive diffusion, controlled by a semi-permeable releasemembrane, or is controlled by the adhesive/adhesive matrix. The systemmay also incorporate drug penetration enhancers to increase the flux ofthe drug through the skin.

One of the drawbacks of the current approaches to administering hormonesand steroids is that the formulations are typically in continuouscontact with the skin. Creams and ointments or adhesives used in patchescan cause skin irritation and sensitisation. A significant proportion ofpatch users suffer from skin irritation and sensitisation due toadhesives used in the patch. Steroids and hormones, particularly the sexsteroidal hormones have a relatively poor skin permeation and manypatches require high loads of drug or large a surface area in order toprovide effective blood levels.

The rate of drug delivery across a dermal surface can be increased bydermal penetration enhancers. The problem with most known dermalpenetration enhancers is that they are often toxic, irritating orallergenic. These enhancers tend to be proton accepting solvents such asdimethylsulfoxide and dimethylacetamide. More recently, 2-pyrrolidine,N,N-diethyl-m-toluamide (Deet), 1-dodecal-azacycloheptane-2-one (Azone),N,N dimethylformamide, N-methyl-2-pyrrolidine and calcium thioglycolatehave been reported as effective enhancers. However, difficulties remainwith because the problem of irritation at the site of application and/ordifficulty in providing sufficient enhancement of transdermelabsorption.

The discussion of documents, acts, materials, devices, articles and thelike is included in this specification solely for the purpose ofproviding a context for the present invention. It is not suggested orrepresented that any or all of these matters formed part of the priorart base or were common general knowledge in the field relevant to thepresent invention as it existed before the priority date of each claimof this application.

SUMMARY

The invention provides a transdermal delivery system comprising acomposition comprising at least one agent selected from hormones andsteroids, and a penetration enhancer comprising a polyethylene glycol ofaverage molecular weight no more than 300.

In a further aspect the invention provides a method of transdermaladministration of an active agent to an animal subject, including ahuman, comprising application to a dermal surface of the animal of theabove described transdermal delivery system.

In yet another aspect the invention provides use of (i) polyethyleneglycol of average molecular weight no more than 300 and (ii) at leastone agent selected from hormones and steroids in manufacture of amedicament for transdermal administration to a subject by application ofthe medicament to an area of the skin surface of the subject.

In one embodiment the medicament may be for treatment of an insufficientlevel of a hormone such as a sex hormone or for contraception.

In a further embodiment the invention comprises a composition comprisinga pharmacological agent selected from steroids and hormones and apenetration enhance for application to an area of skin of a subject. Thecomposition may be for treatment of an insufficient level of a hormonesuch as a sex hormone, for hormone replacement therapy or contraception.

In a further aspect the invention provides a method of preparing atransdermal delivery system for administration to an area of dermalsurface of an animal the method comprising combining at least onepharmacological agent selected from hormones and steroids and apenetration enhancer comprising polyethylene glycol of average molecularweight no more than 300.

In a further embodiment the invention comprises a transdermal deliverysystem comprising a spray apparatus comprising a container for atransdermal composition a spray nozzle and an actuator for delivering ametered dose of spray from the container via the nozzle, wherein thetransdermal composition comprises at least one pharmacological agentselected from hormones and steroids and a penetration enhancer componentcomprising polyethylene glycol of average molecular weight no more than300.

The transdermal delivery system will preferably be applied in a dosesufficient to provide an effective amount of at least onepharmacological agent in the bloodstream of the animal.

Preferably the animal is a human but the invention also extends to thetreatment of non-human animals.

DEFINITIONS

It will be understood by those skilled in the art that the termpolyethylene glycol does not include diethylene glycol (althoughdiethylene glycol may if desired be present as an additional component).Polyethylene glycol of average molecular weight no more than 300includes polyethylene glycol of nominal average molecular weight 200 and300 wherein the average molecular weight is not more than 110% and notless than 90% (preferably not more than 105% and not less than 95%) ofthe nominated value. Polyethylene glycol is of formulaH—[OCH₂CH₂]_(n)—OH. An average molecular weight of no more than 300means the average value of n is at least 3 and is generally from 3 to 6such as 3, 4, 5 or 6 (although the average need not be an integer) andmore preferably 3 to 5. Polyethylene glycol (PEG) is widely availablefrom commercial suppliers in pharmaceutical grades and is sold inspecified nominal molecular weights which generally signify that theaverage molecular weight is not more than 105% and not less than 95% ofthe nominated value. The viscosities and methods for molecular weightdetermination are disclosed in USP NF Official Compendium of StandardsVolume 11180-1182 [2007 Edition].

The term “pharmacological agent” is used herein to refer to a broadclass of useful chemical and therapeutic agents.

The term “pharmacological” in describing the agents contemplated hereinis used in a broad sense to comprehend not only agents having a directpharmacological effect on the host, but also those having an indirect orobservable effect which is useful in the medical arts. The termpharmacological agent includes prodrugs of the agent which in vivoexerts the physiological effect. Steroids encompass compounds having thegeneral cyclopentanoperhydrophenanthrene ring system of formula:

Steroids vary by the functional groups attached to these rings and theoxidation tate of the rings. The steroid may be in the form of theactive drug or may be a prodrug steroid which in vivo provides a moreactive form of the steroid. The steroids include drugs and prodrugswhich provide eutrogenic, androgenic glucocorticoid, adrenocortoid,anabolic or birth control activity. Examples of steroids include, forexample, dexamethasone, dexamethasone acetate, dexamethasone sodiumphosphate, cortisone, cortisone acetate, hydrocortisone, hydrocortisoneacetate, hydrocortisone cypionate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, prednisone, prednisolone, prednisoloneacetate, prednisolone sodium phosphate, prednisolone tebutate,prednisolone pivalate, triamcinolone, triamcinolone acetonide,triamcinolone hexacetonide, triamcinolone diacetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,flunsolide, beclomethasone dipropionate, betamethasone sodium phosphate,betamethasone, vetamethasone disodium phosphate, vetamethasone sodiumphosphate, betamethasone acetate, betamethasone disodium phosphate,chloroprednisone acetate, corticosterone, desoxycorticosterone,desoxycorticosterone acetate, desoxycorticosterone pivalate,desoximethasone, estradiol, fludrocortisone, fludrocortisone acetate,dichlorisone acetate, fluorohydrocortisone, fluorometholone,fluprednisolone, paramethasone, paramethasone acetate, androsterone,fluoxymesterone, aldosterone, methandrostenolone, methylandrostenediol,methyl testosterone, norethandrolone, testosterone, testosteroneenanthate, testosterone propionate, equilenin, equilin, estradiolbenzoate, estradiol dipropionate, estriol, estrone, estrone benzoate,acetoxypregnenolone, anagestone acetate, chlormadinone acetate,fluorogestone acetate, hydroxymethylprogesterone,hydroxynnethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate, melengestrolacetate, normethisterone, pregnenolone, progesterone, ethynyl estradiol,mestranol, dimethisterone, ethisterone, ethynodiol diacetate,norethindrone, norethindrone acetate, norethisterone, fluocinoloneacetonide, flurandrenolone, hydrocortisone sodium succinate,methylprednisolone sodium succinate, prednisolone phosphate sodium,triamcinolone acetonide, hydroxydione sodium, spironolactone,oxandrolone, oxymetholone, prometholone, testosterone cypionate,testosterone phenylacetate, estradiol cypionate, and norethynodrel.

A “prodrug” is a pharmacological drug which is administered in aninactive or less active form and is metabilised into an active form. Theprodrug itself may have little or none of the desired activity until itinteracts with the systems of the body such as the skin or circulatorysystems. Nonetheless hormones and steroids used in the transdermaldelivery system of the invention include hormones and steroids which areprodrugs which on administration form a more active hormone or steroidin vivo during or after the process of transdermal administration.

In yet another preferred embodiment, a prodrug or a composition ofprodrug mixed with the parent composition has a permeation rate that isfaster or slower than an identical composition having apharmacologically equivalent amount of the parent drug. In still anotherpreferred embodiment, the composition has a duration of the therapeuticeffect that is longer or shorter than a composition having apharmacologically equivalent amount of the parent drug alone. In anotherpreferred embodiment, the prodrug is more lipophilic than the parentdrug and the prodrug has a greater permeation rate through the skin.Generally the Prohormones and prosteroids are variations or derivativesof the parent hormones or steroids which have groups cleavable undermetabolic conditions. Prodrugs become the parent drugs which arepharmaceutically active in vivo, when they undergo solvolysis underphysiological conditions or undergo enzymatic degradation. Prodrugscommonly known in the art include acid esters prepared by reaction ofthe parent acids or alcohol with a suitable alcohol or acidrespectively, or amides prepared by reaction of the parent acid or aminecompound with an amine or acid respectively, or basic groups reacted toform an acylated base derivative. Examples of prodrugs are discussed in,Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985;Silverman, The Organic Chemistry of Drug Design and Drug Action, pp.352-401, Academic Press, San Diego, Calif., 1992 and Burger's MedicinalChemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp. 172-178, 949-982(1995). The other method for controlling the blood plasma profile ofsubject is in the selection of the prodrug, such as based on itsmolecular weight or polarity. By increasing the molecular weight of theprodrug, the time to the onset of permeation of effective amounts of theprodrug will increase relatives to the parent drug. One example of thiseffect is in the use of norethindrone and norethindrone acetate. Thepermeation rate of norethindrone rapidly peaks after application,whereas norethindrone acetate having a higher molecular weight reaches amaximum after the norethindrone permeation rate begins to decline,steroids having a free hydroxy group at a position on the steroid ring,such as the 17-position, the 3-position, or at the 11-position on thefused ring. Particularly preferred are steroidal hormones such asestrogens, progestins, and androgens. The corresponding steroid prodrug(prosteroid) is defined as a corresponding structure to the steroidwhere the free hydroxy at the 3,11 or 17 position has been reacted withan alcohol reactive moiety. Particularly preferred are steroidderivatives acylated at the 17 position hydroxyl for example by a C₁-C₁₂alkanoyl group. Regardless of whether the steroid or the correspondingprosteroid derivative is incorporated in the carrier composition as thedominant drug, each provides a source of steroid in the bloodstream toachieve the intended physiological effect which, in the case of thecorresponding prosteroid, occurs through metabolic conversion of thederivative. A steroid ester is the corresponding structure to thesteroid where the free hydroxy group on the ring has been esterified.Examples of a steroid and its corresponding ester include estradiol andestradiol benzoate, estradiol 17-beta cypionate, estradiol 17propionate, estradiol hemisuccinate (eutocol), estradiol enanthate,estradiol undecylate, estradiol acetate, and estradiol proprionate, etc.Another example is testosterone and its corresponding ester oftestosterone such as 17 beta-cypionate, testosterone enanthate,testosterone nicotinate, testosterone phenylacetate, testosteroneproprionate, etc. Also included are non-esters that have groups on the17 position such as testosterone 17-chloral hemiacetal, or ethers thathave groups on the 3-position such as estradiol 3-methyl ether.

The terms “percutaneous” and “transdermal” are used herein in thebroadest sense to refer to being able to pass through unbroken skin.

The term “dermal penetration enhancer” is used herein in its broadestsense to refer to an agent which improves the rate of percutaneoustransport of active agents across the skin for use and delivery ofactive agents to organisms such as animals, whether it be for localapplication or systemic delivery.

The term “non-occlusive” is used herein in its broadest sense to referto not trapping or closing the skin to the atmosphere by means of apatch device, fixed reservoir, application chamber, tape, bandage,sticking plaster, or the like which remains on the skin at the site ofapplication for a prolonged length of time. It is particularly preferredthat the transdermal delivery system of the invention is non-occlusive.

The term “stratum corneum” is used herein in its broadest sense to referto the outer layer of the skin, which is comprised of (approximately 15)layers of terminally differentiated keratinocytes made primarily of theproteinaceous material keratin arranged in a ‘brick and mortar’ fashionwith the mortar being comprised of a lipid matrix made primarily fromcholesterol, ceramides and long chain fatty acids. The stratum corneumcreates the rate limiting barrier for diffusion of the active agentacross the skin.

The term “skin-depot” is used herein in its broadest sense to refer to areservoir or deposit of active agent and dermal penetration enhancerwithin the stratum corneum, whether it be intra-cellular (withinkeratinocytes) or inter-cellular.

The term “volatile:non-volatile liquid vehicle” is used in the art torefer to a liquid pharmaceutical vehicle comprising a volatile liquidmixed with a non-volatile liquid vehicle, such as a dermal penetrationenhancer. A system or vehicle comprising a volatile liquid mixed with anon-volatile dermal penetration enhancer when described herein is usedin its broadest sense to include those systems known as volatile:non-volatile liquid vehicles.

The term “aliphatic” includes straight chain, branched chain and cyclicaliphatic and may be saturated alkyl groups or unsaturated aliphaticcontaining from 1 to 3 unsaturated groups particularly 1 to 3 doublebonds.

The transdermal drug delivery system of the present invention enables awide range of pharmacological agents selected from hormones and steroidsto be delivered through the skin to achieve a desired systemic effect.The drug delivery system preferably comprises at least one active agentintimately mixed with a non-volatile dermal penetration enhancer and avolatile liquid. Where the drug delivery system is applied to the skin,at least one active agent selected from hormones and steroids andnon-volatile liquid are thermodynamically driven into the skin as thevolatile liquid evaporates. Once within the skin the non-volatile liquidmay either disrupt the lipid matrix and/or act as a solubilizer to allowan enhanced penetration rate of the at least one active agent throughthe skin and into the subject being treated. In this way, the dermalpenetration enhancer acts as a vehicle and many systemic active agentsare able to be transdermally administered to an animal.

The subject to be treated with the transdermal delivery system isgenerally a mammal, preferably a human being, male or female. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought.

Throughout the description and the claims of this specification the word“comprise” and variations of the word, such as “comprising” and“comprises” is not intended to exclude other additives, components,integers or steps.

DETAILED DESCRIPTION

The present inventors have found that the use of polyethylene glycol (ofmolecular weight no more than 300) as a penetration enhancer shows asignificant improvement in penetration enhancement of the active agent.

Typically the PEG of average molecular weight less than 300 will bepresent in an amount in the range of from 0.5 to 20% such as 1%, 1.5%,2%, 2.5%, 3%, 3.5%, 4%©, 4.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%,15%, 16%, 17%, 18%, 19%, or 20%. Preferably the PEG of average molecularweight less than 300 is present in an amount in the range of from 0.5 to15% and most preferably from 0.5 to 10% by weight of the composition.

The composition of the invention preferably comprises PEG 200 in anamount in the range of from 0.1 to 40% by weight of the totalcomposition and preferably from 0.5 to 20% such as 1%, 1.5%, 2%, 2.5%,3%, 3.5%, 4%, 4.5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%,17%, 18%, 19%, 20%.

The composition of the invention may and preferably will contain avolatile solvent. Preferably the volatile solvent has a vapour pressureabove 35 mm Hg at atmospheric pressure and normal skin temperature of 32degrees Celsius. In a particularly preferred form of the invention thesolvent preferably is a C₂ to C₄ alkanol and more preferably is ethanolor isopropanol, or a mixture thereof.

The volatile solvent is preferably present in the composition of theinvention in an amount in the range of from 40 to 95% by weight of thecomposition and preferably from 50 to 95%, more preferably from 60 to95% by weight such as 65% to 95% by weight, 70% to 95%, 70 to 90% or 75to 90% by weight of the total composition.

The composition of the invention may if desired contain one or moreadditional adjuvants such as those selected from the group consisting ofpenetration enhancers, surfactants, thickeners and solvents. Examples ofsuitable thickeners include polyacrylic acids; and acylic acidcopolymers, agor, carrageenan, food starch, gelatins, germ Arabic,guorgem, hydroxyethyl cellulose hydroxypropymethyl cellulose, proteinand polyvinyl pyrrolidone. The content of thickener may be from 0 to 5%.

In one embodiment the penetration enhancer component of the compositionmay comprise one or more additional penetration enhancers. Of particularnote are esters of salicylic acid preferably selected from the C₆ to C₃₀aliphatic ester of salicylic acid and more preferably C₈ to C₁₂ alkylsalicylate and most preferably octyl salicylate particularly2-ethylhexyl saliclate. When an ester of salicyclic acid is present incombination with polyethylene glycol, the weight ratio of the ester ofsalicylic acid to the polyethylene glycol (of average molecular weightno more than 300) is preferably in the range of from 95:5 to 5:95 andpreferably from to 1:10 to 10:1 such as 1:10 to 5:1 and 1:5 to 2:1. Theoptimal ratio may vary depending on the nature and concentration of theactive agent and the concentration of the penetration enhancercombination.

Known dermal penetration enhancers may be included in addition to PEG ofmolecular weight no more than 300. Examples of known penetrationenhancers are laurocapram and laurocapram derivatives, such as those1-alkylazacycloheptan-2-ones specified in U.S. Pat. No. 5,196,410, andoleic acid and its ester derivatives, such as methyl, ethyl, propyl,isopropyl, butyl, vinyl and glycerylmonooleate, and those given in U.S.Pat. No. 5,082,866, particularly dodecyl(N,N-dimethylamino) acetate anddodecyl(N,N-dimethylamino) propionate and in U.S. Pat. No. 4,861,764,particularly 2-n-nonyl-1-3-dioxolane. Most preferred known dermalpenetration enhancers are oleic acid and its ester derivatives, such asmethyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate,and those given in U.S. Pat. No. 5,082,866, particularlydodecyl(N,N-dimethylamino) acetate and dodecyl(N,N-dimethylamino)propionate and in U.S. Pat. No. 4,861,764, particularly2-n-nonyl-1-3-dioxolane.

Preferably the composition will comprise no more than 5% by weight ofthe other non-volatile penetration enhancer more preferably no more than1% and most preferably no more than 0.5% by weight of the composition ofnon-volatile penetration enhancers other than PEG of molecular weight ofno more than 300.

In a preferred embodiment of the invention the composition consistsessentially of:

-   -   (i) at least one active selected from hormones and steroids and        more preferably steroidal sex hormones;    -   (ii) a penetration enhancer component consisting essentially of        a polyethylene glycol of average molecular weight no more than        300;    -   (iii) a volatile solvent consisting of one or more of ethanol        and isopropanol;    -   (iv) optionally a propellant.

It will be understood by those skilled in the art that alcohols andpolyols contain a certain amount of water. Typically the total watercontent of the composition is less than 20% by weight and preferablyless than 10% by weight of the total composition.

The composition of the invention may be in a range of forms such as aliquid, cream, paste, gel, lotion, patch (matrix and reservoir), tape,plaster or film former. In the more preferred embodiment the transdermaldelivery system is in the form of a liquid for application to a definedarea of skin.

The compositions of the present invention may be in any form suitablefor topical application to the skin. Suitable forms include sprayableliquids; gels; liquids that may be applied using a roll-on device;lacquers; and sustained release matrices of transdermal delivery devicessuch as patches. The compositions are usually administered alone but,under some circumstances, administration may be further modified byusing other delivery mechanisms such as iontophoresism, ultrasound andmicroneedles to enhance penetration. Non-occlusive application and inparticular spray application is preferred.

Suitable pharmacologically active hormones and steroids may be selectedfrom:

Estrogens such as estradiol, estriol, estradiol benzoate, estradiol17.beta.-cypionate, estradiol enanthate, estradiol propionate, estrone,ethinylestradiol, Fosfestrol, Dienestrol mestranol, stilboestrol,dienoestrol, epioestriol, estropipate Diethylstilbestrol,Chlorotrianisene, conjugated estrogenic hormones, Polyestradiolphosphate and zeranol and mixtures thereof;

Progesterone and progestins such as norethisterone, norethisteroneacetate, gestodene, levonorgestrel, allylestrenol, anagestone,desogestrel, dimethisterone, dydrogesterone, ethisterone, ethynodiol,Ethynodiol diacetate, Etonogestrel, gestodene, ethinylestradiol,haloprogesterone, 17-hydroxy-16-methylene-progesterone,17.alpha.-hydroxyprogesterone, lynestrenol, medroxyprogesterone,melengestrol, norethindrone, norethynodrel, norgesterone, Gestonorone,Norethisterone, norgestimate, norgestrel, Levonorgestrel,norgestrienone, norvinisterone, pentagestrone, MENT(7-methyl-19-testosterone); Norelgestromin, and trimigestoneDrospirenone, Tibolone, and megestrol and mixtures thereof;

Selective progesterone receptor modulators such as Asoprisnil, CDB-4124and mixtures thereof;

Selective estrogen receptor modulators such as Bazedoxifene, Clomifene,Fulvestrant, Lasofoxifene, Raloxifene, Tamoxifen, Toremifene andmixtures thereof;

Antiprogestogen such as Mifepristone and mixtures thereof.

Antigonadotropins such as Danazol and Gestrinone and mixtures thereof;

Antiandrogens such as cyproterone acetate and danazol and mixturesthereof;

Antiestrogens such as tamoxifen and epitiostanol and the aromataseinhibitors, exemestane and 4-hydroxy-androstenedione and its derivativesand mixtures thereof.

Androgens and anabolic agents such as androisoxazole, androstenediol,bolandiol, bolasterone, clostebol, ethylestrenol, formyldienolone,4-hydroxy-19-nortestosterone, methandriol, methenolone,methyltrienolone, nandrolone, norbolethone, oxymesterone, stenbolone andtrenbolone. Androgenic steroids can include boldenone, fluoxymesterone,mestanolone, mesterolone, methandrostenolone, 17-methyltestosterone,17.alpha.-methyltestosterone 3-cyclopentyl enol ether, norethandrolone,normethandrone, oxandrolone, oxymesterone, oxymetholone, prasterone,stanlolone, stanozolol, testosterone, testosterone 17-chloralhemiacetal, testosterone proprionate, testosterone enanthatetiomesterone dehydroepiandrosterone (DHEA), androstenedione (Andro): anandrostenediol, androsterone, dihydrotestosterone (DHT) andandrostanolone and derivatives thereof;

5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704and MK-306 and mixtures thereof;

Corticosteroids such as betamethasone, betamethasone valerate,cortisone, dexamethasone, dexamethasone 21-phosphate, fludrocortisone,flumethasone, fluocinonide, fluocinonide desonide, fluocinolone,fluocinolone acetonide, fluocortolone, halcinonide, halopredone,hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate,hydrocortisone 21-acetate methylprednisolone, prednisolone, prednisolone21-phosphate, prednisone, triamcinolone, triamcinolone acetonide andmixtures thereof;

Further examples of steroidal antiinflammatory agents for use in theinstant compositions include cortodoxone, fluoracetonide,fludrocortisone, difluorsone diacetate, flurandrenolone acetonide,medrysone, amcinafel, amcinafide, betamethasone and its other esters,chloroprednisone, clorcortelone, descinolone, desonide, dichlorisone,difluprednate, flucloronide, flumethasone, flunisolide, flucortolone,fluoromethalone, fluperolone, fluprednisolone, meprednisone,methylmeprednisolone, paramethasone, cortisone acetate, hydrocortisonecyclopentylpropionate, cortodoxone, flucetonide, fludrocortisoneacetate, flurandrenolone acetonide, medrysone, amcinafal, amcinafide,betamethasone, betamethasone benzoate, chloroprednisone acetate,clocortolone acetate, descinolone acetonide, desoximetasone,dichlorisone acetate, difluprednate, flucloronide, flumethasonepivalate, flunisolide acetate, fluperolone acetate, fluprednisolonevalerate, paramethasone acetate, prednisolamate, prednival,triamcinolone hexacetonide, cortivazol, formocortal and nivazol andmixtures thereof;

Aromatase inhibitor such as Aminogluthetimide, Anastrozole, Exemestane,Formestane, Letrozole and Vorozole;

Gonadotropins such as Clomifene and Urofollitropin;

GnRH:(receptor) agonists such as Buserelin, Goserelin, Histrelin,Leuprorelin, Nafarelin and Triptorelin;

GnRH antagonist: Abarelix, Cetrorelix and Ganirelix;

Pituitary hormones and their active derivatives or analogs such ascorticotrophin, thyrotropin, follicle stimulating hormone (FSH),luteinising hormone (LH) and gonadotrophin releasing hormone (GnRH);

Thyroid hormones such as calcitonin, thyroxine and liothyronine andantithyroid agents such as carbimazole and propylthiouracil; and

Other miscellaneous hormone agents such asoctreotide; and mixtures fromtwo or more of the groups.

The optimal ratio of penetration enhancer to active will differdepending on the nature of the active and the penetration enhancer.Typically the weight ratio of penetration enhancer to active will be inthe range of from 1000:1 to 1:1000 and preferably from 500:1 to 1:10 andmost preferably from 20:1 to 1:1.

The penetration enhancer of the invention is particularly useful intransdermal administration of hormones. Hormones that may be used in thedrug delivery system of the present invention include systemicallyactive hormones which can be delivered through the skin with theassistance of the dermal penetration enhancer to achieve a desiredeffect.

Compositions of the invention may include a plurality of hormones fromone or more of these groups. For example it may be desirable forcontraceptive formulations to comprise one or more estrogens and one ormore progestins.

The transdermal delivery system may be used to deliver a therapeuticallyeffective amount of the hormone and/or steroid to a local area or to thesystemic circulation. In one embodiment the system provides apharmaceutically effective level of the pharmacological agent in thesystemic circulation, for example a pharmaceutically effective bloodlevel. In one preferred form of the invention the drug delivery systemcomprises on a weight basis from about 0.1 to about 10% of at least onepharmacological agent selected from hormone and steroids in an amount offrom about 0.1 to 12% of the dermal penetration enhancer and from about78 to 99.8% ethanol, isopropanol or mixture thereof.

In another preferred form of the invention the drug delivery systemcomprises, on a weight basis, from about 1 to 3% of at least onepharmacological agent selected from hormone and steroids in an amount offrom about 1 to 15% of the dermal penetration enhancer combination, fromabout 45 to 90% ethanol, isopropanol or mixture thereof, and 5 to 45%water.

Diseases or conditions that may be treated by using the drug deliverysystem and methods of the present invention include, but are not limitedto, male hormone replacement in testosterone deficient hypogonadal men,female hormone replacement therapy for postmenopausal women using forexample estradiol, androgen replacement therapy for females lackinglibido using an androgen such as testosterone, male contraception (forexample using a progestin such etonogestrel optionally withtestosterone) and female contraception (for example using a progestinoptionally in combination with an estrogen).

In one embodiment the transdermal delivery system comprises a sprayapparatus comprising a container for a transdermal composition, a spraynozzle and an actuator for delivering a metered dose of spray from thecontainer via the nozzle, wherein the transdermal composition comprisesat least one pharmacological agent and a first penetration enhancercomponent of polyethylene glycol of average molecular weight no morethan 300; and optionally a second penetration enhancer component of anester of salicylic acid.

The transdermal delivery system will preferably be applied in a dosesufficient to provide an effective amount of the at least onepharmacological agent in the bloodstream of the animal.

Preferably, the applicator provides a metered dose application such as ametered dose aerosol, a stored-energy metered dose pump or a manualmetered dose pump. Preferably the drug delivery system is applied to theskin of the animal covering a delivery surface area between about 10 and800 cm², more preferably between about 10 and 400 cm², and mostpreferably between about 10 and 200 cm². The application is mostpreferably performed by means of a topical metered dose spray combinedwith an actuator nozzle shroud which together accurately control theamount and/or uniformity of the dose applied. One function of the shroudis to keep the nozzle at a pre-determined height above, andperpendicular to, the skin to which the drug delivery system is beingapplied. This function may also be achieved by means of a spacer-bar orthe like. Another function of the shroud is to enclose the area abovethe skin in order to prevent or limit bounce-back and/or loss of thedrug delivery system to the surrounding environment. Preferably the areaof application defined by the shroud is substantially circular in shape.

The invention will now be described with reference to the followingexamples. It is to be understood that the examples are provided by wayof illustration of the invention and that they are in no way limiting tothe scope of the invention.

EXAMPLES

The compositions of the Examples and their performance are compared withreference to the drawings.

BRIEF DESCRIPTION OF DRAWINGS

In the drawings:

FIG. 1 is a column chart comparing the permeation of a progestin+anestrogen from a control with progestin transdermal delivery compositionof the invention containing PEG-200 pursuant to Example 1.

FIGS. 2 a and 2 b are column charts showing the effect on progestinpermeation of comparative transdermal compositions containing differentprogestins and PEG400 rather than PEG 200 as described in Example 2.

FIG. 3 is a column chart which shows the effect of PEG 200 on thepermeation of an androgen from transdermal delivery compositionsdescribed in Example 3.

FIG. 4 and FIG. 5 are column charts which compare the effect of PEG 200and PEG 400 respectively on permeation of an androgen from transdermaldelivery compositions described in Example 4.

FIG. 6 is a column chart examining the effect of PEG 200 on permeationof an androgen from compositions of Example 5.

FIG. 7 is a column chart examining the effect of PEG 200 on thepermeation of an estrogen from transdermal delivery compositionsdescribed in Example 6.

FIG. 8 is a column chart showing the effect of PEG 200 on the permeationof the androgen testosterone in the presence of another permeationenhancer as described in Example 7.

EXAMPLE 1 Investigation of the Effect of PEG200 on Cumulative Permeationof the progestin Norethisterone Acetate and the Estrogen EstradiolThrough Human Skin In Vitro Methods:

Finite-dose in vitro diffusion studies were undertaken using dermatomedhuman female abdominal skin (500 μm).

These experiments were performed over 24 hours using Franz-type cells.Pre-cut skin membranes were mounted as a barrier between the halves ofgreased (high vacuum grease, BDH) horizontal Franz-type permeation cellsin the middle of the receptor chamber of the cell with the stratumcorneum facing the donor chamber. The area available for permeation wasapproximately 0.925 cm². The receptor chambers of the permeation cellswere filled with the receptor phase (Phosphate Buffered Saline pH 7.4)and capped. The permeation cells were immersed in a constant temperaturewater bath such that the receptor chambers were maintained at 35° C.Receptor chamber contents were continuously agitated by smallPTFE-coated magnetic stirrer bars driven by submersible magneticstirrers. The skin was allowed to equilibrate to temperature withreceptor solution for 1 h in the water bath prior to dosing.

The formulations were applied to the skin at a dose of 3.6 μL/cm². Theapplied formulation was spread over the skin area using an Eppendorfpositive displacement pipette tip without breaking the skin membrane.

The formulations consisted of:—

-   -   Comparison composition 1: 2.8% Norethisterone Acetate (NETA),        0.55% Estradiol (E2), 5% Octyl Salicylate (OS)    -   Composition 2: 2.8% NETA, 0.55% E2, 5% Polyethylene Glycol 200        (PEG200)    -   Composition 3: 2.8% NETA, 0.55% E2, 5% OS, 5% PEG200    -   Composition 4: 2.8% NETA, 0.55% E2, 10% PEG200    -   Composition 5: 2.8% NETA, 0.55% E2, 5% OS, 10% PEG200

The amount of active that permeated the skin was quantified usingvalidated HPLC methods

FIG. 1 compares the penetration of comparative composition 1 withcompositions 2-5 relating to invention. PEG200 in combination with OSwas found to significantly enhance the permeation of both NorethisteroneAcetate and estradiol through human epidermis in vitro. Permeation ofNETA is compared in FIG. 1.

EXAMPLE 2 Investigation Into the Effect of PEG200 and PEG400 onCumulative Nestorone & Ethinylestradiol Permeation Through Human Skin InVitro Methods:

Finite-dose in vitro diffusion studies were undertaken using dermatomedhuman female abdominal skin (500 μm).

These experiments were performed over 24 hours using stainless steel,flow through diffusion cells based on those described previously(Cooper, E. R. J. Pharm. Sci. 1984, 73, 1153-1156) except that the cellwas modified to increase the diffusion area to 1.0 cm². The formulationswere applied using a finite dose technique (Franz, T. J. Curr. Probl.Dermatol., 1978, 7, 58-68) to mimic clinical dosing conditions at anapplied dose volume of 3.6 μL/cm². A piece of stainless steel wire meshwas placed directly below the skin in the receptor chamber of the of thediffusion cell to maintain a turbulent flow of receptor solution belowthe skin. The diffusion cells were maintained at a flow rate ofapproximately 0.5 mL/hr by a microcassette peristaltic pump (WatsonMarlow 505S UK). The cells were kept at 32±0.5° C. by a heater bar andthe samples were collected into appropriately sized glass vials for aperiod of 24 hr. The receptor solutions (Phosphate Buffered SalinepH7.4) maintained sink conditions below the skin.

The formulations consisted of:—

-   -   Composition (Comp) 1 (Control): 1.35% Nestorone (NES), 0.35%        Ethinylestradiol (EE) in Isopropyl Alcohol (IPA)    -   Comp 2: 1.35% NES, 0.35% EE, 5% Polyethylene glycol 400 (PEG400)        in IPA Comp 3: 1.35% NES, 0.35% EE, 0.5% Polyethylene glycol        (PEG200) in IPA

The amount of active that permeated the skin was quantified usingvalidated HPLC methods.

The effect of PEG400 on permeation of NES and EE is shown in FIGS. 2 aand 2 b respectively. FIGS. 2 a and 2 b: thus show Nestorone andEthinylestradiol permeation respectively obtained from the applicationof Composition 2 (not of the invention) compared against application ofa control composition 1.

PEG200 in combination with OS was found to enhance the permeation ofboth Nestorone and Ethinylestradiol through human epidermis in vitro.

The addition of PEG400 to the formulation did not have a significanteffect (enhancing or inhibitory) on the permeation of Nestorone throughhuman epidermis in vitro. PEG400 was found to inhibit the permeation ofethinylestradiol through human epidermis in vitro.

EXAMPLE 3 Investigation into the Effect of PEG200 on CumulativeTestosterone Permeation Through Human Skin In Vitro Methods:

Finite-dose in vitro diffusion studies were undertaken using dermatomedhuman female abdominal skin (500 μm).

These experiments were performed over 24 hours using stainless steel,flow through diffusion cells based on those described previously(Cooper, E. R. J. Pharm. Sci. 1984, 73, 1153-1156) except that the cellwas modified to increase the diffusion area to 1.0 cm². The formulationswere applied using a finite dose technique (Franz, T. J. Curr. Probl.Dermatol., 1978, 7, 58-68) to mimic clinical dosing conditions at anapplied dose volume of 3.6 μL/cm². A piece of stainless steel wire meshwas placed directly below the skin in the receptor chamber of the of thediffusion cell to maintain a turbulent flow of receptor solution belowthe skin. The diffusion cells were maintained at a flow rate ofapproximately 1.0 mL/hr by a microcassette peristaltic pump (WatsonMarlow 505S UK). The cells were kept at 32±0.5° C. by a heater bar andthe samples were collected into appropriately sized glass vials for aperiod of 24 hr. The receptor solutions (0.002% w/v NaN₃) maintainedsink conditions below the skin.

The formulations consisted of:—

-   -   Comp 1: 5% Testosterone (TES), in ethanol (95%)    -   Comp 2: 5% TES, 1.0% polyethylene glycol 200 (PEG200) in ethanol        (95%)    -   Comp 3: 5% TES, 2.5% PEG200 in ethanol (95%)

The amount of active that permeated the skin was quantified usingvalidated HPLC methods.

The effect of the combination of PEG200 in Compositions 2 and 3 iscompared with a control Composition 1 in FIG. 3 As shown in FIG. 3,PEG200 in was found to significantly enhance the permeation ofTestosterone through human epidermis in vitro.

EXAMPLE 4 Investigation into the Effect of PEG200 and PEG 400 onCumulative Permeation of the AndrogenTestosterone from a Lotion ThroughHuman Skin in Vitro Methods:

Finite-dose in vitro permeation studies were undertaken using dermatomedskin (Padgett Model B or S electric dermatome set at 500 μm) preparedfrom excised female, abdominal tissue.

These experiments were conducted over 24 hours (h) using flow-throughsystems with a 1-cm² administration area. A piece of stainless steelwire mesh was placed in the receptor chamber of each permeation cell tosupport the skin and to maintain a turbulent flow of receptor solutionbelow the skin. The receptor solution was maintained at a flow rate ofapproximately 0.5 mL/hr by a peristaltic pump (Watson Marlow 520SPeristaltic Pump with 313A adaptor and 308MC 8 roller pump-head; StauffCorporation, Australia). The cells were placed on a heater bar to keepthe temperature of the skin at 32±1° C.

Following a 2-h equilibration of the skin with the receptor solution(RS; 0.002% sodium azide), the stratum corneum surface was dosed witheither 15 or 30 μL/cm² of an MD-Lotion formulation using a positivedisplacement pipette. The formulation was spread evenly over the skinarea using the pipette tip. Permeation samples were collected intoappropriately sized glass vials for a period of 24 h.

The effect of the addition of Polyethylene glycol 200 (PEG200) orPolyethylene glycol 400 (PEG 400) on the permeation of testosterone wasinvestigated. 0.5-5% w/v PEG200 or PEG 400 was added to the followingTestosterone (TES) Lotion formulation:—

-   -   Formulation: 2% w/v TES, 2% w/v polyvinylpyrrolidone (PVP) in        isopropyl alcohol (IPA).

The amount of active that permeated the skin was quantified usingvalidated HPLC methods. Results for PEG 200 are shown in FIG. 4 andresults for PEG 400 are shown in FIG. 5.

Results:

PEG200 significantly enhanced the permeation of TES through human skinin vitro. PEG400 did not have any effect on the permeation of TESthrough human skin in vitro.

EXAMPLE 5 Investigation into the Effect of PEG200 and PEG 400 onCumulative Permeation of the Androgen Testosterone Through Human Skinfrom a Transdermal Testosterone Composition Applied as a Spray in VitroMethods:

Finite-dose in vitro permeation studies were undertaken using dermatomedskin (Padgett Model B or S electric dermatome set at 500 μm) preparedfrom excised female, abdominal skin.

These experiments were conducted over 24 hours (h) using flow-throughsystems with a 1-cm² administration area. A piece of stainless steelwire mesh was placed in the receptor chamber of the of each permeationcell to support the skin and to maintain a turbulent flow of receptorsolution below the skin. The receptor solution was maintained at anominal flow rate of 0.5 mL/h by a peristaltic pump (Watson Marlow 520SPeristaltic Pump with 313A adaptor and 308MC 8 roller pump-head; StauffCorporation, Australia). The cells were placed on a heater bar to keepthe temperature of the skin at 32±1° C.

Following a 2-h equilibration of the skin with the receptor solution(RS; 0.002% sodium azide), the stratum corneum surface was dosed with3.6 μL/cm² of a Metered Dose Transdermal Spray (MDTS) formulation usinga positive displacement pipette. The formulation was spread evenly overthe skin area using the pipette tip. Permeation samples were collectedinto appropriately sized glass vials for a period of 24 h.

The Metered Dose Transdermal Spray formulations contained:

-   -   Testosterone (TES), Polyethylene glycol 200 (PEG 200) or        Polyethylene glycol 400 (PEG 400) isopropyl alcohol (IPA).

The amount of active that permeated the skin was quantified usingvalidated HPLC methods and the results for PEG 200 are shown in FIG. 6.

Results:

PEG200 increased the permeation of TES through human skin in vitro. Theaddition of Adding PEG 400 to the formulation did not result in anysignificant difference in the permeation of TES when compared with thecontrol formulation.

EXAMPLE 6 Estradiol Spray: Investigation into the Effect of PEG200 andPEG 400 on Estradiol Permeation Through Human Skin in Vitro Methods:

Finite-dose in vitro permeation studies were undertaken using dermatomedskin (Padgett Model B or S electric dermatome set at 500 μm) preparedfrom excised female, abdominal skin.

These experiments were conducted over 24 hours (h) using flow-throughsystems with a 1-cm² administration area. A piece of stainless steelwire mesh was placed in the receptor chamber of the of each permeationcell to support the skin and to maintain a turbulent flow of receptorsolution below the skin. The receptor solution was maintained at anominal flow rate of 0.5 mL/h by a peristaltic pump (Watson Marlow 520SPeristaltic Pump with 313A adaptor and 308MC 8 roller pump-head; StauffCorporation, Australia). The cells were placed on a heater bar to keepthe temperature of the skin at 32±1° C.

Following a 2-h equilibration of the skin with the receptor solution(RS; 0.002% sodium azide), the stratum corneum surface was dosed with3.6 μL/cm² of an Estradiol Transdermal Spray formulation using apositive displacement pipette. The formulation was spread evenly overthe skin area using the pipette tip. Permeation samples were collectedinto appropriately sized glass vials for a period of 24 h.

The Estradiol Transdermal Spray formulations contained:—

-   -   Testosterone (TES), Polyethylene glycol 200 (PEG 200) or        Polyethylene glycol 400 (PEG 400) isopropyl alcohol (IPA)

The amount of active that permeated the skin was quantified usingvalidated HPLC methods and the results are depicted in FIG. 7.

Results:

In both the 0.25% and the 0.50% formulations PEG200 was found to enhancethe permeation of Estradiol through human skin in vitro.

EXAMPLE 7 Investigation into the Effect of PEG200 on CumulativeTestosterone Permeation Through Human Skin in Vitro Methods:

Finite-dose in vitro diffusion studies were undertaken using dermatomedhuman female abdominal skin (500 μm).

These experiments were performed over 24 hours using stainless steel,flow through diffusion cells based on those described previously(Cooper, E. R. J. Pharm. Sci. 1984, 73, 1153-1156) except that the cellwas modified to increase the diffusion area to 1.0 cm². The formulationswere applied using a finite dose technique (Franz, T. J. Curr. Probl.Dermatol., 1978, 7, 58-68) to mimic clinical dosing conditions at anapplied dose volume of 15 μL/cm². A piece of stainless steel wire meshwas placed directly below the skin in the receptor chamber of the of thediffusion cell to maintain a turbulent flow of receptor solution belowthe skin. The diffusion cells were maintained at a flow rate ofapproximately 1.0 mL/hr by a microcassette peristaltic pump (WatsonMarlow 505S UK). The cells were kept at 32±0.5° C. by a heater bar andthe samples were collected into appropriately sized glass vials for aperiod of 24 hr. The receptor solutions (0.002% w/v NaN₃) maintainedsink conditions below the skin.

The formulations consisted of:—

-   -   Comp 1: 2% Testosterone (TES), 5% Octyl Salicylate (OS), 2%        polyvinyl pyrrolidine (PVP), 30% isopropyl alcohol (IPA) in        ethanol (95%)    -   Comp 2: 2% TES, 5% OS, 2% PVP, 30% IPA, 0.5% polyethylene glycol        200 (PEG200) in ethanol (95%)    -   Comp 3: 2% TES, 5% OS, 2% PVP, 30% IPA, 1.0% PEG200 in ethanol        (95%)    -   Comp 4: 2% TES, 5% OS, 2% PVP, 30% IPA, 2.5% PEG200 in ethanol        (95%)

The amount of active that permeated the skin was quantified usingvalidated HPLC methods

The effect on permeation of TES from using the composition as shown inFIG. 8. PEG200 was found to significantly enhance the permeation ofTestosterone in combination with the permeation enhancer octylsalicylate (OS) through human epidermis in vitro.

1.-18. (canceled)
 19. A transdermal delivery system comprising acomposition comprising at least one pharmacological agent selected fromhormones and steroids; a penetration enhancer comprises a polyethyleneglycol (PEG) of average molecular weight no more than 300; and a solventselected from C₂ to C₄ alkanol and mixtures thereof in an amount in therange of from 70% to 95%, by weight of the total composition.
 20. Atransdermal delivery system according to claim 19, wherein the PEG ofaverage molecular weight of no more than 300 is present in an amount ofat least 0.1% by weight of the total composition.
 21. A transdermaldelivery system according to claim 19, wherein the PEG of averagemolecular weight of no more than 300 is present in the range of from0.5% to 20% by weight of the total composition.
 22. A transdermaldelivery system according to claim 19, wherein the composition consistsessentially of: (i) at least one pharmacological agent selected fromhormones and steroids; (ii) the penetration enhancer componentconsisting of a polyethylene glycol of average molecular weight no morethan 300; (iii) a volatile solvent consisting of one or more of ethanoland isopropanol; and optionally a propellant.
 23. A transdermal deliverysystem according to claim 19, wherein the total water content of thecomposition is less than 10% by weight of the total composition.
 24. Atransdermal delivery system according to claim 19, which isnon-occlusive.
 25. A transdermal delivery system according to claim 19,wherein the weight ratio of penetration enhancer to pharmacologicalagent is in the range of from 20:1 to 1:1.
 26. A transdermal deliverysystem according to claim 19, wherein at least one pharmacological agentcomprises one or more selected from the group consisting of steroidalhormones.
 27. A transdermal delivery system according to claim 19,wherein at least one pharmacological agent comprises one or moresteroids which provide eutrogenic, androgenic glucocorticoid,adrenocortoid, anabolic or birth control activity.
 28. A transdermaldelivery system according to claim 27, wherein the pharmacological agentcomprises one or more steroids selected from the group consisting ofdexamethasone, dexamethasone acetate, dexamethasone sodium phosphate,cortisone, cortisone acetate, hydrocortisone, hydrocortisone acetate,hydrocortisone cypionate, hydrocortisone sodium phosphate,hydrocortisone sodium succinate, prednisone, prednisolone, prednisoloneacetate, prednisolone sodium phosphate, prednisolone tebutate,prednisolone pivalate, triamcinolone, triamcinolone acetonide,triamcinolone hexacetonide, triamcinolone diacetate, methylprednisolone,methylprednisolone acetate, methylprednisolone sodium succinate,flunsolide, beclomethasone dipropionate, betamethasone sodium phosphate,betamethasone, vetamethasone disodium phosphate, vetamethasone sodiumphosphate, betamethasone acetate, betamethasone disodium phosphate,chloroprednisone acetate, corticosterone, desoxycorticosterone,desoxycorticosterone acetate, desoxycorticosterone pivalate,desoximethasone, estradiol, fludrocortisone, fludrocortisone acetate,dichlorisone acetate, fluorohydrocortisone, fluorometholone,fluprednisolone, paramethasone, paramethasone acetate, androsterone,fluoxymesterone, aldosterone, methandrostenolone, methylandrostenediol,methyl testosterone, norethandrolone, testosterone, testosteroneenanthate, testosterone propionate, equilenin, equilin, estradiolbenzoate, estradiol dipropionate, estriol, estrone, estrone benzoate,acetoxypregnenolone, anagestone acetate, chlormadinone acetate,fluorogestone acetate, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, hydroxyprogesterone,hydroxyprogesterone acetate, hydroxyprogesterone caproate, melengestrolacetate, normethisterone, pregnenolone, progesterone, ethynyl estradiol,mestranol, dimethisterone, ethisterone, ethynodiol diacetate,norethindrone, norethindrone acetate, norethisterone, fluocinoloneacetonide, flurandrenolone, hydrocortisone sodium succinate,methylprednisolone sodium succinate, prednisolone phosphate sodium,triamcinolone acetonide, hydroxydione sodium, spironolactone,oxandrolone, oxymetholone, prometholone, testosterone cypionate,testosterone phenylacetate, estradiol cypionate, and norethynodrel andthe salts and prodrugs thereof.
 29. A transdermal delivery systemaccording to claim 19, for female contraception comprising a comprisingone or more estrogens and one or more progestins.
 30. A transdermaldelivery system according to claim 19, wherein the drug delivery systemcomprises on a weight basis from about 0.1 to about 10% of the steroidor hormone, from about 0.1 to 12% of the penetration enhancer and fromabout 70 to 99.8% ethanol, isopropanol or mixture thereof.
 31. Atransdermal delivery system according to claim 19, further comprising aspray apparatus comprising a container containing the transdermalcomposition, a spray nozzle and an actuator for delivering a metereddose of spray from the container via the spray nozzle.
 32. A transdermaldelivery system according to claim 19, for transdermal administration ofat least one pharmacological agent selected from hormones and steroids.33. The transdermal delivery system according to claim 32, wherein thetransdermal administration is by application of the medicament to anarea of dermal surface of a subject.
 34. The transdermal delivery systemaccording to claim 32, wherein the subject is in need of male hormonereplacement in testosterone deficient hypogonadal men, female hormonereplacement therapy for postmenopausal women, or androgen replacementtherapy for females lacking libido or suffering depression using anandrogen, male contraception, or female contraception.
 35. A method ofpreparing a transdermal delivery system comprising a composition foradministration to an area of dermal surface of a subject, the methodcomprising combining at least one pharmacological agent selected fromhormones and steroids and a penetration enhancer comprising polyethyleneglycol of average molecular weight no more than 300 and 70% to 95%, byweight of the total composition of solvent selected from C₂ to C₄alkanols and mixtures thereof.